Derivatives of 5-oxo-1{62 -cyclopentaneheptanoic acid, 5-ethylene acetals and method of preparation

ABSTRACT

Racemic or optically active prostaglandin E1 is synthesized from racemic or optically active precursors in good yield at the various steps from 3 Alpha ,6,7,7 Alpha -tetrahydro-4-methyl-2oxo-1 Beta -indaneheptanoic acid methyl ester proceeding through 2 Alpha -(2-carboxyethyl)-3 Beta -hydroxy-5-oxo-1 Beta cyclopentaneheptanoic acid methyl ester, delta -lactone, 5cyclic ethylene acetal, 2 Alpha -(2-carboxy-2-formylethyl)-3 Beta -hydroxy-5-oxo-1 Beta -cyclopentaneheptanoic acid methyl ester, delta -lactone, 5-cyclic ethylene acetal, 2 Alpha -(2-carboxy-2oxoethyl)-3 Beta -hydroxy-5-oxo-1 Beta -cyclopentaneheptanoic acid methyl ester, delta -lactone, 5-cyclic ethylene acetal, and 3 Beta -hydroxy-2 Alpha -(3-oxo-1-octenyl)-5-oxo-1 Beta cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal.

i United Stati Wendler et al.

Taub

DERIVATIVES or S-OXO-lB-CYCLOPENTANEHEPTANOIC ACID, S-ETHYLENE ACETALSAND METHOD OF PREPARATION Inventors: Norman L. Wendler, Summit; DavidTaub, Metuchen; Harry L. Slates, Westfielcl; Zbigniew S. Zelawsld,Piscataway, all of NJ Assignee: Merck & Co., Inc., Rahway, NJ.

Filed: Jan. 23, 1974 Appl. No.: 435,812

Related U.S. Application Data Division of Ser. No. 20L979. Nov. 24,l97l, Pat. No. 3.833.612.

U.S. Cl. 260/3403 Int. Cl. CO'I'D 3l7/26 Field of Search 260/3409References Cited OTHER PUBLICATIONS et al, Chemical Communications (Eng)D,

Oct. 28, 1975 1970. pp. I258 and Primary Examiner-Richard L. RaymondAllorney, Agent, or Firm-J. Jerome Behan; David L. Rose; Thomas E.Arther ABSTRACT Racemic or optically active prostaglandin E issynthesized from racemic or optically active precursors in good yield atthe various steps from 3a,6,'7 7atetrahydro-4-methyl-2-o xolB-indaneheptanoic acid methyl ester proceeding throughZa-(Z-carboxyethyh- 3 B-hydroxy-S-oxol B-c yclopentaneheptanoic acidmethyl ester, 5-lactone, S-cyclic ethylene acetal, 2a- (2-carboxy-2formylethyl )Jflhydroxy-Scxol B- cyclopentaneheptanoic acid methylester, S-lactone, S-cyclic ethylene acetal, 2a-(2-carboxy-2-oxoethyl)- 3B-hydroxy-S-oxol B-cyclopentaneheptanoic acid methyl ester, S-lactone,S-cyclic ethylene acetal, and 3B-hydroxy-2a-( 3-oxol -octenyl )-5-oxol Icyclopentaneheptanoic acid methyl ester, S-cyclic ethylene acetal.

3 Claims, No Drawings 3915.994 3 4 (c11 cooR (c11 coon (c11 cooR lCHCOOR 0 Cll OC 0 g l o o n (CH (POOR in the foregoing formulas R and R,represent hydrogen, loweralkyl or aralkyl; R, represents hydrogen or anacetyl group, and R and R represent hydrogen or acyl. The loweralkylgroups of the invention are those containing from I to 6 carbon atomssuch as methyl, ethyl. propyl, and hexyl. The acyl groups of thisinvention are loweralkanoyl groups of from 2 to 6 carbon atoms such asacetyl, propionyl. butyryl, hexanoyl. and the like. and monocyclic aroylgroups such as benzoyl. toluoyl. and the like. The aralkyl groups aredefined as loweralkyl groups substituted with an aromatic group of from6 to l0 carbon atoms. Preferred are benzyl. xylyl and the like.

As a matter of convenience for understanding the foregoing flowsheet andthe following description of the invention. there follows a list ofnames of the chemical compounds l-l0 inclusive.

(CH COOZ'l 0H (cg co0tt HO H l (l\',=CH)311,6.7,7a-tetrahydroJ-mctyl-Z-oxmlindaneheptanoic acid methyl ester.2cydc etluyh-e acetal.

S5 2. (R,=Ch,, R H) 3-acetyl-2a-lZ-cIrbOKyethyU-S-oxo-lB-cyclopentaneheptanoic acid methyl ester. 5- cyclic ethyleneacetal.

'.R.=R,=CH,)

cyclopentaneheptanoic acid methyl or. S-cyclic ethylene acetal.

3. (R,=R,=CH,, 3B-aoeoxy-2a-[2- methoxycarbonyl) ethgdl-S-oxo-l}cyclopentaneheptanoic acid methyl estar. S-cycic ethylene acetal.

3. lR,=R,=CH R, =H) Za-I Z-mcthoxycurbtmylelhylI-3B-hydroxy-5=oxo-l[3-cyclopentanehep.anoic acid methyl ester. S-cyclicethylene acetal.

DERIVATIVES F S-OXO-lB-CYCLOPENTANEHEPTANOIC ACID, S-ETHYLENE ACETALSAND METHOD OF PREPARATION This is a division of application Ser. No.201.979, filed Nov. 24. l97l. now U.S. Pat. No. 3.833.6l2.

BRIEF SUMMARY OF THE INVENTION This invention relates to a new and novelsynthesis of prostaglandin E and more particularly to a synthesis whichhas a high degree of stereoselectivity at the points of generating theasymmetric centers of the mol- DETAILED DESCRlPTlON OF THE INVENTIONProstaglandin E., which may be depicted structurally H /OH (c11 c0011\c/ H C is one of a group of naturally occurring compounds knowngenerally as prostaglandins. These prostaglanlCll l CooR l1 --'l1 R OOC---ll C11 n O CH 0 (CI-l COOR (CH COOR I! R OOC H 11 ---II R O 1 O..

dins have interesting and important biological activity. the precisebiological properties varying with the individual members of theprostaglandin family, as described in the article Prostaglandins. byP.W. Rarnwell et al.. Progress in the Chemistry of Fats and OtherLipids. Vol. IX. Polyunsaturated Acids. Part 2. pp. 231-273. PergamonPress I968).

One of the more important prostaglandins is prostaglandin E also knownas PGE,. It has an effect on the contractility of smooth muscle and isuseful in the induction of labor in pregnant females and for thetermination of pregnancies by therapeutic abortion. MP. Embrey. BritishMedical Journal. 1970. 2. 256-258; 258-260. Other uses. besidesstimulation of smooth muscle. are described in the literature andinclude the lowering of blood pressure. effect on the mobilization offree fatty acids from adipose tissue. inhibition of lipolysis. andbronchodilating effects.

Heretofore. the supply of prostaglandin E,. as well as of otherprostaglandins. has been severely limited because only minute amounts ofnaturally occurring material are available. and partial biosynthesis byenzymes present in mammalian seminal vesicles has only afforded limitedamounts of the products.

An object of this invention is to provide a stereoselective synthesis of(i) prostaglandin E which compound has one-half the biological activityof the naturally occurring PGE,. and prostaglandin E. which compound hasl00% of the biological activity of naturally occurring POE and which maybe used for the same biological effects as the natural compound.

A further object of the invention is to provide novel intermediatecompounds some of which. in addition to being useful in the synthesis of(t) and PGE,. may themselves exhibit prostaglandin-like activity. Anadditional object is to provide a stereoselective total synthesis of theother members of the prostaglandin group which may be prepared by knownmethods from 2 and prostaglandin E Thus. for instance. (1:)prostaglandin F may be obtained by reduction of (i) PGE,. Other objectswill become evident from the following description of the invention.

The novel process and intermediates of our invention are shownstructurally in the following flow diagram. and immediately followingthis diagram the chemical names of the compounds are set forth.

(CH2) Coon 4. (R,=CH;,)Za-(Z-carboxyethyl)-3fl-hydroxy-5-oxocyclopentaneheptanoic acid methylester. 8-lactone. S-cyclic ethylene acetal. v

5. (R,=CH,) 2a-(2-carboxy-2-2-formylethyll-JB-hydroxy-S-oxo-lB-cyclopentaneheptanoic acid methyl ester. 6-Iactone.S-cyclic ethylene acetal.

5A. 2a-( 2-Carboxy-2-oxoethyl )-3,B-hydroxy-$-oxol B-cyclopentaneheptanoic acid methyl ester. lHactone,

S-cyclic ethylene acetal.

(R.=Cl-l,, R =acetyl) 2a-(2-acetoxy-2- carboxyvinyl)-3fi-hydroxy-$-oxo-I B- cyclopentaneheptanoic acid methyl ester. fi-lactone. $cyclicethylene acetal.

7. (R,=Cl-l,)Za-formyl-IlB-l(methoxalyDoxyll-S-oxolB-cyclopentaneheptanoic acidmethyl ester. 5- cyclic ethylene acetal.

7A. (R,=CH,) 3fl-l(methoxyalyl)oxyl-]2a-(3-oxo-loctenyl )-5-oxolfi-cyclopenaneheptanoic acid methyl ester. S-cyclic ethylene acetal.

8. (R.=CH R,=H) 3B-hydroxy-2a-t3-oxo-l-octenyU-S-oxo-lfi-cyclopentaneheptanoic acid methyl ester. S-cyclic ethyleneacetal.

9. (R,=CH;,. R,=H) Prostaglandin E, methyl ester. cyc

lic ethylene acetal.

9. (R,=R,=H) Prostaglandin E.. cyclic ethylene acute l0. ProstaglandinE,. t

in the foregoing list of names and in subsequent discussions. the estersand acyl groups have been referred to as methyl esters and acetyl groupsrespectively because the detailed examples refer to such groups; but itis to be understood that other esters are within the scope of theinvention as show: by the symbols Rhd l,

R,, R and R. in the flow diagram.

The synthesis of prostaglandin E, in its racemic (it or natural formstarts with 3a,6,7.7a-tetrahydro' 4- methyl-Z-oxo-lB-indane..eptanoicacid methyl ester (1. R 32 CH in its rucemic or optically active form.

In the first step of this synthesis either racemic or optically active30,0.7,7a-tetrahydr-4-methyl-I-oxu-l8 indaneheptanoic acid methyl esterl R,#IH,J is converted to 3a,6.7,7a-tetrahydro-4-mcthyl-2-oxo-lB-indat-cheptanoic acid methyl ester. cyclic ethylene acetal by eactionwith ethylene glycol in the presence of an acid such asp-toluene-sulfonic acid. The resulting acetal is then oxidized with anoxidizing agent such as potassium permanganate preferably in thepresence of sodium periodate. to produce 3-acetyl-2a-(2-carboxyethyU-S-oxo-ltS-cyclopentaneheptanoic acid methyl ester. S-cycticethylene acetal (2. R,=Cl-l,. R,=H). It is preferred to includepotassium carbonate in the reaction system which facilitates theoxidation as well as partially epimerizing the 3-carbon atom such thatthe macetyl group becomes a fl-acetyl group. The reaction product is amixture of Ila-acetyl and 3B- acetyl-2a-( 2-carboxyethyl )-5-oxol B-cyclopentaneheptanoic acid methyl ester. ScycIic ethylene acetal (2R,=CH,, R,=H

The epimeric mixture is then treated with an excess of adiazoloweralltane or diazoaralkane to prepare the ester derivative whichis then epimerized, forming the 3B-acetyl group from the 3a-acetylgroup, with an alkali metal loweralkoxide. preferably the same alkoxidegroup present on the ester functions in order to prevent transccrification. In order to accomplish this the epimeric mixture isdissolved in a loweralkanol and treated with a loweralkunol solution ofthe alkali metal ylene acetal (3. R =R,=CH,. R,=acetyl). The reactionmixture is generally buffered with a weakly alkalin'e buffering agentsuch as sodium monohydrogen phos-- phate. The reaction is run generallyat room temperature for from it) to 30 hours. Thin layer chromatographyof an aliquot portion indicates the degree of complction of the reactionand additional oxidizing agent ma, be added if necessary until thereaction is complcte.

('ompound 3(R,=R,=CH,. R,=acetyl) is treated with All alkali metalalkoxide in the corresponding loweralkuiml. The reaction is run for froml to 4 hours at about room temperature and worked up by techniques knownto those skilled in the art affording 201-] 2- methoxycarbonylethyl]-3Bhydr0xy-5-oxo-lB- cyclopentaneheptanoic acid methyl ester, S-cyclicethylene acetal (3. R,=R =CH,. R,=H). The hydroxy compound is thenlactunized with an alkali metal alkoxide preferably potassium t-butoxidein an inert solvent such as benzene, toluene. and the like at the refluxtemperature of the solvent employed. The solvent is preferably one whichcodistills with the loweralkanol corresponding to R,

Distillation of the solvent is continued until a thin layer chromatogramof an aliquot indicates conversion to lactone 4 is complete. Thisnormally requires from I to 6 hours of distillation. There is recovered2a-(2- carboxyethyl )-3B-hydroxy-5-ox0- IB- cyclopentaneheptanoic acidmethyl ester. 5-lactone. S-cyclic ethylene acetal (4. R,=CH,).

The next step in the racemic or optically active synthesis is theformylation of compound 4 with a loweralkyl formate in the presence ofan alkali metal hydride at from 0 to 40C. for from la to 6 hours. Theexothermal nature of the reaction usually necessitates adding the alkalimetal hydride portionwise and maintaining the temperaure at from 0' to10 during the first hour of the reaction. The product isZa-(Z-carrboxy-Z- formylethyl)-3fi-hydroxy-5-oxol cyclopentaneheptanoicacid methyl ester. fi-lactone, S-cyclic ethylene acetal sodium salt.which on treatment with a mild acid such as sodium dihydrogen phosphatein aqueous solution liberates compound 5- The formyl derivative isozonized in the presence of an organic base such as pyridine attemperatures substantially below 0C.. preferably dry ice temperatures.by bubbling ozone or a mixture of O, and 0, into the reaction mixtureuntil an excess is present. indicated by the presence of a pale bluecolor. The resulting 2a-(2- carboxy-Z-oxoethyl)-3fi-hydroxy-5-oxoIB-cyclopentaneheptanoic acid methyl ester. b-lactone. S-cyclic ethyleneacetal (5A. R,=CH,) which is isolated but not purified is reacted withan acylating agent in the presence of an organic base. Preferred areacetylating agents as acetic anhydride. acetyl chloride. and the like.however. other acylating agents such as benzoyl chloride may beutilized.-The reaction is worked up by techniques known to those skilledin the artyielding 2a-(2-acetoxy-2-carboxyvinyl)-3B-hydroxy-S-oxo-lB-cyclopentaneheptanoic acid methyl ester. fi-lactone.S-cyclic ethylene acetal (6, R.=CH,.

R.=acetyl).

in the next step the above acyl compound is oxidized with osmiumtetroxide in the presence of an alkali metal periodate in methanol. Thecompound is treated first with the osmium tetroxide until the solutiondarkens. The alkali metal periodate. perferably sodium periodate is thenadded portionwise over from 2 to 6 hours and the reaction stirred atabout room tempeature for from 2 to 6 hours, affording 2a-formyl-3B-[(methoxalyl )oxyl-S-oxol B-cycloppentaneheptanoic acid methyl ester.S-cyclic ethylene acetal (7. R.=CH

A Wittig reaction is employed to form the octenone side chain at the2-position of the cyclopentane ring. The formyl compound (7. R,=CH; istreated with an alkali metal hydride and dimethyl 2-oxoheptylphosphonatein an anhydrous. inert solvent. such as tetrahydrofuran. dioxane, andthe like. The intermediate 35-[(methoxyalyl)oxyl-Za-(Zl-oxo-l-octenyl)-5-oxo-lB- cyclopentaneheptanoicmethyl ester. S-cyclic ethylene acetal (7A. R,=CH is treated with al.2-diamine such as ethylene diamine at from -l to 25C. for from 15minutes to 2 hours cleaving the 3B-methoxalyl-oxy group and affording3B-hydroxy-2a-(3-oxo-l-octenyl)- -oxo-lB-cyclopentaneheptanoic acidmethyl ester. 5-

cyclic ethylene acetal (8. R,=CH;. R,==H).

The side chain keto group is reduced to a hydroxyl group with a mildreducing agent such as an alkali metal borohydride. The reduction iscomplete in from minutes to 2 hours at from to C. The reaction affords amixture of the R and S stereoisomers because both B and a-hydroxy groupsare formed. of which the a=-hydroxy is preferred. The reaction mixtureis chromatograhed whereupon the isomers are separated and pureprostaglandin E methyl ester-5-cyclic ethylene acetall3B-hydroxy-2a:-(Ba-(SI-hydroxy-loctenyl)-S-oxo-lB-cyclopentaneheptanoicacid methyl ester. S-cyclic ethylene acetal. (9. R CH R,=H)] isobtained. The 3BlRlhydroxy compound is separately obtained from thechromatographic column. and back oxidized by treatment with manganesedioxide to afford the keto starting material (8. R.=CH,. R,=H) which canbe recycled.

It is advantageous to employ the O-acyl. preferably the acetylderivative of the 3B-hydroxyl group of compound 8 during the reductionand back oxidation of the side chain keto group. The acyl group has nodeleterious effects on the reduction to the hydroxyl group. However,yields are considerably improved during the back-oxidation of the [R]hydroxyl group with manganese dioxide if the acyl group is present.

The final steps in this synthesis of racemic or optically active POE,involves the removal of the protecting groups. The esters are hydrolizedto the free acid using base-catalyzed hydrolysis in aqueous media. Preferred catalysts are alkali metal hydroxides such as potassium hydroxidein aqueous solution at from 0 to 40C. for from l to 5 hours. The thusproduced prostaglandin E -5-cyclic ethylene acetal (9. R,-=H. R,=H)

is treated with an aqueous acid preferably an organic acid such asacetic acid. at about room temperature or from i to 5 hours. cleavingthe cyclic acetal and yielding prostaglandin E,.

Depending on whether the starting material (compound l l is racemic oroptically active. racemic or optically active PGE will be obtained. Noloss in optical activity is observed when optically active (I) isemployed; the reaction sequence (1 thru (10) being stereoselective andnot tending to the racemization of any of the intermediates.

There are two series of optically active intermediates. one leading toPOE, and the other to PGE The former is the naturally occurring form ofPOE and the one which possesses all of the biological activity. Bothseries of intermediates can be prepared using the procedures of thefollowing examples. The series of intermediates leading to the naturallyoccurring PGE. is preferred and when referred to hereinbelow are termedof the natural series."

The following examples are presented in order that the invention mightbe more readily understood. They should not be constured as beinglimitative of the invention.

Examples l-P through 18-? describe the preparation of the startingmaterial of the instant application and of the resolution of theintermediates into desired stereoisomer resulting in either the racemic(z) or optically active starting material viz 3a.6.7.7a-tetrahydro4-methyl-2-oxo-indaneheptanoic acid methyl ester.

EXAM PLE l-P Zia-M ethyl-4-cyclohexene-l a,2a-dimethanol A solution of25 g. of (z)-3a-methyl-4-cyclohexenela,3a-dicarboxy|ic anhydride in ml.of dry tetrahydrofuran is added to a suspension of 10.5 g. of lithiumaluminum hydride in 140 ml. of tetrahydrofura'n at such a rate as tomaintain a gentle reflux. When the addition is complete the reactionmixture is refluxed for 3 hours and allowed to cool overnight. Thecomplex is decomposed by the careful addition of I00 ml. of hitetrahydrofuran/water mixture to the reaction mixture at 0C. I50 Ml. ofchloroform is added. the reaction mixture is filtered. and the filtercake washed with chloroform. The combined filtrates are concentrated todryness in vacuo. The residue is dissolved in benzene. dried withmagnesium sulfate. and evaporated affording 22.4 g. of (i) Bwmethyll-cyclohexene-l12.2mdimethanol as a colorless solid (m.p. 47-49.5).

When in the above procedure the resolved acid/ester3a-methyl-4-cyclohexene-1a.,2a-dicarboxylic acid l-methyl ester isemployed in place of 3a-methyl-4- cyclohexene-la,3a-dicarboxylicanhydride there is obtained 3a-methyl-4-cyclohexene-[01.20:- dimethanollul CHCl, -26.

EXAMPLE 2-P 3a-Methyl-4-cyclohexenel a,2a-dimethanol-di-p-toluene-sulfonate To a solution of If) g. (0.064 moles) of(t) Bumethyl-4-cyclohexene-la,2a-dirnethanol in 30.4 g. of dry pyridineat l 5C. is added 26.83 g. (0.14] moles, l0% excess) of recrystallizedp-toluenesulfonylchloride in portions at such a rate that thetemperature does not exceed -5C. The reaction mixture is stirred for 2hours at 5 and stored overnight at 4C. The reaction mixture is thenpoured slowly onto 250 cc of an ice/water mixture with stirring. Theaqueous mixture is aged at to C. for 20 minutes and the aqueous layerdecanted from the semi-solid precipitate. The solid material isdissolved in chloroform and the chloroform solution is washed withdilute hydrochloric acid at 0C.. water dilute aqueous potassiumbicarbonate. water again. and finally with saturated aqueous sodiumchloride. The chloroform solution is dried with magnesium sulfate andevaporated to dryness affording 27.7 g. of

a viscous oil which crystallizes on dilution with ether.

3a-methyl-4-cyclohexenel a.,2a-

has a m.p.

The product. (1') dimethanol-di-p-toluene-sulfonate 62.5-65C.

When in the above procedure 3a-methyl-4- cyclohexene-la.2ct-dimethanolis employed in place of the racemic mixture there is obtained3a-methyl-4- :yclohexene-la,2a-dimethanol di-p-toluene sulfonate. m.p.52-54C. [01],, CHCl; l2.

EX A M PLE 3A-P 3a-Methyl-4-cyclohexenel a.2a-diacetonitrile Asuspension of l g. of sodium cyanide and I0 ml. of drieddimethylsulfoxide is heated under nitrogen to 80-85C. 2.37 G. of z)3a-methyl-4-cyclohexenela.2a-dimethanol di-p-toluenesulfonate is addedin 3 portions over l5 minutes and the reaction mixture heated at 90-95C.for IS hours. The reaction mixture is cooled and diluted with 6 volumesof saturated sodium chloride solution. The aqueous mixture is extractedwith methylene chloride, dried with magnesium sulfate, and evaporated todryness in vacuo affording 0.78! g. of (t)3a-methyl-4-cyclohexene-101.20:- diacetonitrile which is obtained as anoil.

E XA M PLE 3B-P 3a-Methyl-4-cyclohexenel a,2a-diacetonitrile Asuspension of [4.7 g. of sodium cyanide and 140 ml. of drieddimethylsulfoxide is heated under nitrogen to 80-85C. 27.7 g. of (I)3a-methyl-4-cyclohexenela,2a-dimethanol di-p-toluenesulfonate is addedin 3 portions over minutes and the reaction mixture heated at 90-95C.for l8 hours. The reaction mixture is cooled. and diluted with 6 volumesof saturated sodium chloride solution. The aqueous mixture is extractedwith methylene chloride; the extracts washed with saturated sodiumchloride, dried with magnesium sulfate, and evaporated to dryness invacuo affording l0.04 g. (96%) of (z) 3a-methyl-cyclohexene-[(1,201-diacetonitrile which is obtained as an oil.

When in the above procedure 3ct-methyl-4- cyclohexenel a,2a-dimethanoldi-p-toluenesulfonate is employed in place of the racemic mixture thereis obtained 3a-methyl-4-cyclohexenel a,2adiacetonitrile which isobtained as an oil.

EX AM PLE 4-? 3a-Methyl-4-cyclohexene-lc.2a-diacetic acid 81.7 G. of(:t) 3a-methyl-4-cyclohexene-lc.2adiacetonitrile is suspended in 700 ml.of 33% aqueous potassium hydroxide and refluxed for 7 hours. Afterstanding overnight at room temperature. the reaction mixture is treatedwith charcoal. extracted with ether. and acidified with concentrated HClaffording a solid precipitate weighing 92 g. The solid material isrecrystalized from acetone/ethylacetate affording 67 g. of (3:)3a-methyl-4-cyclohexene-la.2a-diacetic acid. m.p. l48-l5lC.

When in the above procedure 3a-methyl-4-cyciohexane-la,2a-diacetonitrile is employed in place of the racemicmixture. there is obtained 3amethyI-4-cyclohexene-l0:,2a-diacetic acid.m.p. 98.5-100C., [al CHCl 55.

EXAMPLE S-P 4a-Hydroxy-5B-iodo-3a-methyll 01.20:- cyclohexanediaceticacid S-lactone l2.8 G. of (1') 3a-methyl-4-cyclohexene-l0:,2adiaceticacid is dissolved in ISO ml. of water containing 36 g. of potassiumbicarbonate. A solution of 30.68 g. of iodine and 65.2l g. of potassiumiodide in ISI ml. of water is added with stirring. The reaction mixtureis stirred for 3.5 hours in the dark. decolorized with saturated aqueoussodium bisulfite. acidified with 2.5 N hydrochloric acid. and extractedwith ethyl acetate. The extracts are washed with an aqueous saturatedsodium chloride solution containing a small amount of sodium bisulfite.and evaporated to dryness affording 20.04 g. of (I)4a-hydroxy-5B-iodo-3a-methyl-la,2acyclohexanediacetic acid fi-lactonem.p. l50l$2C.

When in the above procedure 3a-methyl-4- cyclohexenediacetic acid isemployed in place of the racemic mixture. there is obtained4a-hydroxy5fiiodo-3a-methyl-la,2a-cyclohexanediacetic acid 6-lactone.m.p. l70(dec) [al CHCl,-30.

EXAMPLE 6-p 4a-Hydroxy-Sfi-iodo-3a-methyl-l(1.2acyclohexanediacetic acidli-lactone methyl ester 10.0 G. of (1)4a-hydroxy-5B-iodo-3a-methylla,2acyclohexanediacetic acid vS-lactone isdissolved in the minimum amount of methanol and cooled to 0C. Etherealdiazo methane is added dropwise maintaining the temperature at 10C. orless until a yellow color persists in the reaction medium. The solventsare evaporated in vacuo and the residue recrystallized from ethanolaffording (z) 4a-hydroxy-5B-iodo3a-methylla,2a-cyclohexanediacetic acidfi-lactone methyl ester m.p. -82C.

When in the above procedure 4a-hydroxy-SB-iodo-3a-methyl-ln.2a-cyclohexanediacetic acid -8-lac tone is employed inplace of the racemic mixture. there is obtained optically active4a-hydroxy-5fl-iodo-3amethyl-ln.2a-cyclohexanediacetic acid 5-lactone.methyl ester an an oil.

EXAMPLE 7-P 4a-Hydroxy3a-methyl-la.2acyclohexanediactic acid methylester. o-lactone To 68 G. of freshly prepared chromium diacetatedispersed in 250 ml. of dry dimethylsulfoxide containing 40 ml. ofethylmercaptan is added a solution of 20 g. of (t)4a-hydroxy-SB-iodo-Ila-methyl l (1,21:- cyclohexanediacetic acidB-lactone methyl ester in 60 ml. of dimethylsulfoxide over 10 minutes.The reaction mixture isstirred at room temperature for 1% hours anddiluted with 600 ml. ofice water. The reaction mixture is acidified with250 ml. of 2.5 N hydrochloric acid. The solution is further diluted with600 ml. of

EXAMPLE 8 -P 4a-Hydroxy-3a-methyll a,2a-cyclohexanediacetic acidS-lactone 32 G. (0.l4 moles) of (.t)4a-hydroxy-3a-methylla,2a-cyclohexanediacetic acid methyl ester.8-lactone is saponified by stirring under nitrogen at room temperatulefor 1 hour with [5.84 g. (0.28 moles} of potassium hydroxide in 283 ml.of water. The resulting solution is extracted with ether. acidified with2.5 N hydrochloric acid. and extracted with ethyl acetate. The combinedextracts are washed with aqueous Na,S,O, solution. and saturated sodiumchloride solution. and dried over magnesium sulfate. The organicsolution is evaporated to dryness affording 27.52 g. of (1)4ahydroxy-Ila-methyl-la,2a-cyclohexanediacetic acid 8-lactone m.p.l35-l39. Following recrystallization from an acetone/ether mixture. them.p. is raised to When in the above procedure4a-hydroxy-3amethyl-la,2a-cyclohexanediacetic acid methyl ester.5-lactone is employed in place of the racemic mixture there is obtained4a-hydroxy-3a-methyl-la,2a-

cyclohexanediacetic acid. 8-lactone. m.p. ll8-l20.5C.. [0:1 CHCl, 55.

EXAMPLE 9-P 4a-Hydroxy-3a-methyll a,2a-cyclohexanediacetic acid Amixture of 7.0 g. of (t) 4a-hydroxy-3a-methylla,2a-cyclohexanediaceticacid 8-lactone in 70 ml. of water with l4 g. of potassium hydroxide isheated on a steam bath under nitrogen for 2.5 hours. The gaseous carbondioxide is passed through the solution until the pH is 8.0. The reactionmixture is then acidified to a pH of 2 with dilute hydrochloric acid andextracted with ethyl acetate affording 8.32 g. of (t)4a-hydroxy-3amethyl- 1 q,2a-cyclohexanediacetic acid m .p. l5l-l 53C.

When in the above procedure4a-hydroxy-3amethyl-la,2a-cyclohexanediacetic acid. 8-lactone isemployed in place of the racemic mixture, there is obtained()-4a-hydroxy-3a-methyl-l a,2acyclohexanediacetic acid [a], CHCl, 66.

EXAMPLE l0-P da-Hydroxy lia-methyll a,2a-cyclohexanediacetic aciddimethyl ester Following the procedure of Example 6 employing l0.0 g. of(i) 4a-hydroxy-3a-methyl-l0.2acyclohexanediacetic acid there is obtainedz) 40:-

acid

EXAMPLE II -P 4a-Hydroxy 3a-methyl-lmZa-cyclohexaanediacetic aciddimethyl ester methanesulfonate To a stirred solution of 28.95 ml. ofmethane sulfoityl chloride in 50 ml. of dry pyridine at 0C. is added asolution of l l g. of 4a-hydroxy-3a-methyl-l(1.2acyclohexanediaceticacid dimethyl ester in 86 ml. of dry pyridine dropwise. The reactionmixture is stirred for A hour at 0C. and allowed to stand overnight at0C. The reaction is poured onto ice-water and extracted with chloroform.The combined extracts are acidified with dilute HCl at 0C. and washedwith water, potassium bicarbonate solution, water. and saturated sodiumchloride solution. The organic layer is dried with magnesium sulfate andevaporated to dryness affording l4.4 g. of 4a-hydroxy-3a-methyl-lu,2acyclohexanediacetic acid dimethyl estermethanesulfonate obtained as an oil.

EXAMPLE l2 -P 3-Methyl-3-cyclohexene-la,2a-diacetic acid dimethyl esterEXAMPLE l3-P 3-Methyl-3-cyclohexenel a,2a-diacetic acid dimethyl ester7.667 Of 4a-hydroxy-3a-methyl-la,2acyclohexanediacetic acid dimethylester in 16 ml. of dry benzene is added dropwise, at 0, to a stirredsolu tion of 3.95 g. of methanesulfonyl chloride in 77 ml. of drypyridine. After storing the mixture overnight at 0', it is stirred atroom temperature for 6 hours followed by heating at l00-l05 for 16hours. The mixture is well chilled, diluted with hexane and acidified topH with 6 N hydrochloric acid. After separation of the two phases theaqueous layer is reextracted with hexanebenzene mixture. The combinedextracts are washed with water, potassium bicarbonate solution, andsaturated sodium chloride solution, and dried over magnesium sulfate.The solution is evaporated to dryness affording 6.78 g. of3-methyl-3-cyclohexene-la,2adiacetic acid dimethyl ester as an oil.

When in Examples ll and i3 4a-hydroxy'3amethyl-la,2a-cyclohexanediaceticacid. dimethyl ester is employed in place of the racemic mixture thereis obtained 3-methyl-3-cyclohexene-la,2a-diacetic acid dimethyl ester asan oil.

EXAMPLE l4-P 3-Methyl-3-cyclohexene-lmZa-diacetic acid A mixture of0.2403 g. of 3-methyl-3- cyclohexane-la,2a-diacetic acid dimethyl ester.2 ml. of methanol, 2.5 ml. of water, and 0.48 g. of potassium hydroxideis stirred under nitrogen at room temperature overnight. Excess methanolis removed in vacuo and the basic aqueous medium extracted with ether.cooled, acidified with 2.5 N hydrochloric acid, to pH 4 salted out. andextracted with ethyl acetate. Com-' bined extracts after washing withsaturated sodium chloride solution. drying over magnesium sulfate andevaporating to dryness afforded 0. l 894 g. of solid acid, which onrecrystallization from ether-hexane mixture had m.p. l2l-l22.5C.

When in the above procedure 3-methyl-4- cyclohexane-la,2a-diacetic acid.dimethyl ester is employed in place of the racemic mixture there isobtained 3-methyl-3-cyclohexene-la,2a-diacetic acid m.p. l02.5-l04C.[a], CHCI,-99.6.

The above or diacid is converted to the corresponding diester using theprocedure of Example 6.

EXAMPLE l-P 3a.,6.7.7a-Tetrahydrol a-( methox ycarbonyl )-4-methyl-2-oxo-indaneheptanoic acid methyl ester Under an anhydrous andinert atmosphere 36.83 mi. of 0.565 M potassium-t-butoxide in dryt-butanol is evaporated to a white powdery residue under reducedpressure. The dry powder is dispersed in 50 ml. of dry xylene. 5 G. of3-methyl-3-cyclohexene-la,2adiacetic acid dimethyl ester in 40 ml. ofxylene is added to the above dispersion dropwise. The reaction mixtureis brought to reflux with the simultaneous removal by distillation ofthe lower boiling components. Refluxing at the temperature of boilingxylene is then continued for 2 hours. 45 Ml. of excess xylene isdistilled off and 6.]8 g. (10% molar excess) of methyl-7- iodoheptanoatein 5 ml. of xylene is added. The reaction mixture is refluxed for [6hours. cooled, and diluted with benzene. Solid potassium iodide isremoved by filtration recovering 99% of theory. The clear organicfiltrate is washed with saturated sodium chloride, dried over magnesiumsulfate. and evaporated to dryness affording 7.3 g. of3a,6.7,7a-tetrahydro-la- (methoxycarbonyl)-4-methyl-2-oxoindaneheptanoicacid methyl ester which is used as is in the next reaction.

When in the above procedure 3-methyl-3- cyclohexene-l0:,2a-diacetic aciddimethyl ester is employed in place of the racemic mixture there isobtained 301,6 .7 ,7a-tetrahydro- I a- (methoxycarbonyl)-4-methyl-2-oxoindaneheptanoic acid methyl ester.

EXAM PLE l6-P 3a,6.7,7a-tetrahydro-4-methyl-2-oxol B- indaneheptanoicacid methyl ester A stirred mixture of 7.3 g. of 3a,6.7,7a-

tetrahydrol a-( methoxycarbonyl )-4-methyl-2- oxoindaneheptanoic acidmethyl ester and 2l.27 g. of

lithium iodide dihydrate in l20 ml. of s-collidine under a nitrogenatmosphere is refluxed for l l hours. The reaction mixture is evaporatedand concentrated in a high vacuum to remove the s-collidine. The residueis dispersed in ethyl acetate and acidified with 2.5 N hydrochloric acidand salted out with solid sodium chloride. The organic layer isseparated and washed with saturated sodium chloride solution. Thecombined aqueous layers are reextracted with ethyl acetate and thecombined ethyl acetate extracts dried over a magnesium sulfate affordingthe heptanoic acid intermediate. The acid is dissolved in a minimumamount -of methanol and treated with excess ethereal diazome'thane as inExample 6 affording 6.5 g. of 3a,6,7,7a-

tetrahydro-4-methyl-2-oxolB-indaneheptanoic acid methyl ester.

When in the above procedure 3a,6.7.7a-

tetrahydrol a-( methox ycarbonyl l-4-methyl-2- oxoindaneheptanoic acid,methyl ester is employed in place of the racemic mixture there isobtained 3a.- 6.7 .7 a-tetrahydro-4-methyl-2-oxol a-indaneheptanoicacid. methyl ester [al CHCl, +l l .6.

EXAMPLE 17-! Resolution of 3a-methyl-4-cyclohexene-Ia-Za-dicarboxylicacid l-methyl ester 4.98 O. (0.03 moles) of 3a-methyl-4-cyclohexene-lain-dicarboxylic anhydride is dissolved in I00 ml. ofanhydrous methanol and cooled to 0C. The reaction mixture is treatedwith 20 ml. of L35 N sodium methoxide in methanol. The methanol isevaporated in vacuo, the residue is acidified with sodium dihydrogenphosphate. and the 3a-methyl-4- cyclohexene-la.2a-dicarboxylicacid-l-methyl ester extracted with ether, dried. evaporated, andrecrystallized from ether yielding 3.] 5 g. m.p. l l0-l 12C. The acidester is resolved by treating 0.594 g. (0.003 moles) in i0 ml. of etherwith 0.856 g. of(+) dehydroabietylamine in [0 ml. of ether. Theprecipitated solid is recrystallized from acetone affording 0.53 g. of asalt m.p. l63l65C. The salt is converted to the free acid by extractinga suspension of the salt in ether/ethyl acetate with aqueous sodiumbicarbonate. The aqueous solution of the sodium salt of the acid istreated with sodium dihydrogen phosphate precipitating the free acid.The solid material is dried affording 3a-methyl-4- cyclohexenela,2a-dicarboxylic acid- I -monomethyl ester m.p. 60-6lC. [r11 CHCI, 69.

The mother liquor of the initially precipitated salt is concentratedcausing the additional precipitation of a salt m.p. HIP-C. which ontreatment above afforded 3a-methyl-4-cyclohexene-2.2adicarboxylicacid-l-monomethyl ester [01],, CHCl, +67.7.

The above acid ester is reduced following the proce dure of Example 1affording 3a-methyl-4-cyclohexenela,2a-dimethanol in optically activeform.

EXAMPLE l8-P Resolution of 4a-hydroxy-3a-methylla,2a-cyclohexanediaceticacid G-Iactone 53.95 G. of 4a-hydroxy-3a-methyl la.2acyclohexanediaceticacid S-lactone is dissolved in the t crystals m.p. l48-l50C. Therecrystallized salt is suspended in ethyl acetate and extracted withaqueous potassium bicarbonate solution. The aqueous extract is washedwith ether, acidified with 2.5 N hydrochloric acid. saturated withsodium chloride. and the free optically active4a-hydroxy-3a-methyl-l01.201- cyclohexanediacetic acid 8-lactone isextracted with ethyl acetate. The extracts are washed with a saturatedsodium chloride solution, dried over magnesium sulfate. and evaporatedto dryness, affording of crystallineda-hydroxy-Zia-methyl-la,2a-cyclohexanediacetic acid. fi-lactune m.p.ll8-l 20.5C. lul CHCI, 54.7.

The first crop of salt crystals may also be recrystallized affording37.77 g. of crystals m.p. l69-I70.5C. This salt is treated in a similarmanner as above affording 4a-hydroxy-3a-methyl-la,2acyclohexanediaceticacid. 8-lactone m.p. ll8-l20.5C. [01],, CHCL, +55.

EXAMPLE I 3a,6.7.7cr-tetrahydro-4-methyl-2-oxo- IB- indaneheptanoic acidmethyl ester. 2-cyclic ethylene acetal A mixture of l l.8 g. of(z)-3a,6.7,7a-tetrahydro-4- methyl-Z-oxo-lfl-indaneheptanoic acid methylester. 27 ml. of ethylene glycol and 300 mg. of p-toluene sulfonic acidmono-hydrate in 600 ml. of benzene is refluxed with stirring for 18hours using a Dean-Stark trap to separate the water formed in thereaction. The reaction mixture is cooled and added to 300 ml. of cold 5%potassium bicarbonate. The layers are separated and the aqueous layerextracted twice with 2:l benzene-hexene. The combined organic fractionsare washed 3 times with saturated aqueous sodium chloride. dried oversodium sulfate and evaporated to dryness afl'ording 12.6 g. of(:)-3a,6.7.7a-tetrahydro-4- methyl-Z-oxo-lB-indaneheptanoic acid methylester, 2-cyclic ethyiene acetal; nmr (C D.)83.56 [4H- ethylene group].

When in the above procedure (+)-3a,6.7.7atetrahyd ro-4-methyl-2-oxolB-indaneheptanoic acid methyl ester {011 """'l+l L6 is employed in placeof the racemic mixture there is obtained optically active-30:,6.7.7a-tetrahydro-d-methyl-2-oxo-l8- indaneheptanoic acid methylester. 2-cyclic acetal I a b -26.

EXAMPLE 2 3B-Acetyl-2a-( Z-methoxycarbonylethyl )-5 -oxol8-cyclopentaneheptanoic acid methyl ester. S-cyclic ethylene acetal A.3-Acetyl-2a-( Z-carboxyethyl l-S-oxol cyclopentaneheptanoic acid methylester. S-cyclic ethylene acetal To a stirred solution of 5.69 g. of(i)-3a.6.7.7atetrahydro-4-methyl-2-oxo-lB-indaneheptanoic acid methylester. Z-cyclic ethylene acetal in 410 ml. of tbutanol and l 1 ml. ofwater is added a mixture ol'5.80 g. of potassium carbonate. 22.8 g. ofsodium periodate, and 270 mg. of potassium permanganate in 1230 ml. ofwater. The reaction mixture is stirred at 2025C. for 20 hours andconcentrated in vacuo to remove the tbutanol. Ethylene glycol (0.5 ml.)is added and the reaction mixture extracted with lzl ether-benzene toremove neutral material. The aqueous layer is acidified with solidsodium dihydrogen phosphate and extracted 4 times with l:l ethylacetate-benzene. The organic layer is dried over sodium sulfate andevaporated to dryness in vacuo affording (+)-3-acetyl-2a-(2'carboxyethyU-S-oxo-lB-cyclopentaneheptanoic acid methyl ester. S-cyclicethylene acetal as a mixture of the 30: and 3B isomers.

B. 3B-Acetyl-2a-(Z-methoxycarbonylethyl)-5-oxo-lB- cyclopentaneheptanoicacid methyl ester. S-cyclic ethylene acetal The above(:)-3-acetyl-2a-(Z-carboxyethyl)-5-oxolB-cyclopentaneheptanoic acidmethyl ester, S-cyclic ethylene acetal is dissolved in 10 ml. of etherand treated with etheral diazomethane until an excess is present asindicated by a persistent yellow color. After 5 minutes the reactionmixture is evaporated to dryness in vacuo and the residue dissolved in20 mi. of methanol and 2 ml. of 1N sodium methoxide in methanol isadded. The reaction mixture is stirred for 18 hours at room temperatureand added to cold saturated aqueous sodium dihydrogen phosphate. Themethanol is removed in vacuo and the mixture extracted with l:l ethylacetate-benzene. The organic extract is dried 5 over sodium sulfate andevaporated to dryness affording(:)-3B-acetyl-2a-(Z-methoxycarbonylethyl)-5-oxo-lB-cyclopentaneheptanoic acid methyl ester. 5- cyclic ethyleneacetal. nmr (CDCL) 6213 [3H-CH- C0].

When in the above procedures()-3a,6.7.7atetrahydro-4-methyl-2-oxo-lB-indaneheptaniic acid methylester. Z-cyclic ethylene acetal is employed in place of the racemiccompound there is obtained lB-cyclopentaneheptanoic acid. methyl ester.S-cyclic ethylene acetal. [a] +6.8.

EXAMPLE 3 3B-Acetoxy-2a-( Z-methoxycarbonylethyl )-5-oxol B-cyclopentaneheptanoic acid methyl ester. S-cyclic ethylene acetal 60 G.of solid disodium monohydrogen phosphate is added to a stirred solutionof 4.50 g. of (+)-3B-acetyl- 2a-(Z-methoxycarbonylethyl)-5-oxo-1B-cyclopentaneheptanoic acid methyl ester. S-cyclic ethylene acetal in 25ml. of methylene chloride and the mixture cooled to 0C. Ml. of freshlyprepared 0.3M

tion is complete. The reaction is filtered. the precipitate washed withmethylene chloride and the combined filtrates washed with cold aqueouspotassium iodide and cold aqueous sodium thiosulfate to remove residualperacid. The organic extract is washed with water. dilute aqueouspotassium bicarbonate and saturated aqueous sodium chloride. The organiclayer is dried over sodium sulfate and evaporated to dryness in vacuoaffording (t)-3B-acetoxy-2a-(2-methoxycarbonylethyl)--oxo-lficyclopentaneheptanoic acid methyl ester.S-cyclic ethylene acetal as a colorless oil. nmr (CDCI;)62.0I

[3H-CH,COO].

When in the above procedure (+)-3B-acetyl-2a(2- methoxycarbonylethyl)-5-oxol B- cyciopentaneheptanoic acid methyl ester. S-cyciic ethyleneacetal is employed in place of the racemic mixture there is obtainedoptically active 3B-acetoxy-2u- (Z-methoxycarbonylethyl)-5-oxo-lB-cyclopentaneheptanoic acid methyl ester, S-cyclic ethylene acetal. ofthe natural series.

EXAMPLE 4 2a-(Z-Carboxyethyl)-3B-hydroxy-5-oxo1,6- cyclopentaneheptanoicacid methyl ester. fi-lactone. 5-cyclic ethylene acetal A. 2a-(Z-methoxycarbonylethyl)-3B-hydroxy-5-oxol B- cyclopentaneheptanoic acidmethyl ester. S-cyclic ethylene acetal 6 MI. of LOON sodium methoxide isadded to a stirred solution of 4.25 g. of (:)-3B-acetoxy-2a-(2-methoxycarbonylethyl)-5-oxo-IB- cyclopentaneheptanoic acid methyl ester.S-cyclic ethylene acetal in 25 ml. of methanol under a nitrogenatmosphere and stirred at room temperature for 2 hours. The reactionmixture is poured into excess cold saturated aqueous sodium dihydrogenphosphate and extracted with It] ethyl acetate-benzene. The organicextract is dried over sodium sulfate and evaporated to dryness in vacuo.The residue is purified chromatographically employing 180 g. of silicagel and eluting with 25% acetone in chloroform affording pure (t)-2a-(2-methoxycarbonylethyl )-3B-hydroxy-5 oxol B- cyclopentaneheptanoicacid methyl ester. S-cyclic ethylene acetal.

When in the above procedure optically active-3B- acetoxy-2a-(Z-methoxycarbonylethyl J-S-oxo- IB- cyclopentaneheptanoic acid methylester. S-cyclic ethylene acetal of the natural series is employed inplace of the racemic mixture there is obtained (+)-2a-(2-methoxycarbonylethyl )-3B-hydroxy-$-oxol B- cyclopentaneheptanoic acidmethyl ester, S-cyclic ethylene acetal [a] ""'-"I+l4.7.

B. 2a-( 2-Carboxyethyl )-3B-hydroxy-5-oxol cyclopentaneheptanoic acidmethyl ester. S-Iactone. S-cyclic ethylene acetal 1.66 G. of (I)-2a-(Z-methoxycarbonylethyl)-3B- hydroxy5-oxo-IB-cyclopentaneheptanoic acidmethyl ester. S-cyclic ethylene acetal is dissolved in 350 ml. of

benzene in a nitrogen atmosphere and rendered anhy' drous by removing 30ml. of benzene by distillation. 0.25 Ml. of 0.66M potassium t-butoxidein t-butanol is added and an additional [40 ml. of benzene removed bydistillation over a period of 4 hours. The reaction mixture is cooled.added to cold saturated aqueous sodium dihydrogen phosphate. andextracted with benzene. The combined organic layers are washed withsaturated aqueous sodium chloride. dried over sodium sulfate. andevaporated to dryness in vacuo affording (+)-2a-( 2-carboxy-ethyl)-3B-hydroxy-5-oxol B- cyclopentaneheptanoic acid methyl ester.a-lact'one. S-cyclic ethylene acetal as a pale yellow oil.

When in the above procedure (+)-2a-( 2methoxycarbonylethyli-3B-hydroxy-5-oxo-lflcyclopentaneheptanoic acidmethyl ester. 5-cyclic ethylene acetal is employed in place of theracemic mixture there is obtained optically active 2a-(2-carboxyethyl)-3B-hydroxy-5-oxo-1B- cyclopentaneheptanoic acid methylester. B-lactone. 5-cyclic ethylene acetal of the natural series.

EXAMPLE 5 2a-( 2-carboxy-2-formylethyl i-3B-hydroxy-5-oxol B-cyclopentaneheptanoic acid methyl ester. S-Iactone. 5cyclic ethyleneacetal 2l0 Mg. of 50% sodium hydride dispersion is added to a stirredsolution of 1.36 g. of (:)-2a-(2- carboxyethyl)JB-hydroxy-S-oxo-IB-cyclopentaneheptanoic acid methyl ester. 8IQCIODE. 5-cyclic ethyleneacetal in 25 ml. of methyl formate under a nitrogen atmosphere over aperiod of 3 minutes at 0C. The reaction mixture is stirred for 1 hour at0C. and 4 hours at 20C. The solvent is removed in vacuo and the residuetriturated with ether and the precipitate filtered and washed withether. The precipitate is dissolved in cold saturated aqueous sodiumdihydrogen phosphate. extracted with ethyl acetate. dried over sodiumsulfate and evaporated to dryness. The residue is crystallized fromether-hexane affording (:)-2a-(2- carboxy-Z-formylethyl )-3B-hydroxy-5-oxol B- cyclopentaneheptanoic acid methyl ester. 8-lactone. S-cyclicethylene acetal, m.p. 8890'C.

When in the above procedure opptically active-2a-(2-carboxyethyl)Jfi-hydroxy-S-oxo-lflcyclopentaneheptanoic acid methylester. 8-lactone. S-cyclic ethylene acetal of the natural series isemployed in place of the racemic mixture, there is obtained opticallyactive 2a-(2-carboxy-2-formylethyl)-3B-hydroxy-5-oxolB-cyclopentaneheptanoic acid methyl ester. S-lactone.S-cyclic ethylene acetal. of the natural series. m.p. -8l.

EXAMPLE 6 2a-( Z-acetoxy-Z-carboxyvinyl )-3B-hydroxy-5-oxolficyclopentaneheptanoic acid methyl ester. S-Iactune.

* S-cyclic ethylene acetal A. 2a-( 2-carboxy-2-oxoethyl )-3B-hydroxy-5-oxol B- cyclopentaneheptanoic acid methyl ester. 8-lactone. S-cyclicethylene acetal A solution of 460 mg. of (:)-2fl-(2-carboxy-2-formylethyl)-3fl-hydroxy-5-oxo-lflcyclopentaneheptanoic acid methylester. S-Iactone. S-cyclic ethylene acetal in 6 ml. of methylenechloride and 4.4 ml. of pyridine is cooled to 70C. and treated with a 5%ozone-oxygen mixture until an excess of ozone is present as indicated bya persistent pale blue color. The excess ozone is evaporated by bubblingnitrogen into the reaction and the solvents are removed in vacuo. Theresidue is triturated with ether affording crystalline til-20:4Z-carboxy-Z-oxoethyl )-3B- hydroxy-S-oxol fi-cyclopentaneheptanoic acidmethyl ester. 8-lactone. S-cyclic ethylene acetal. m.p. ll4"-l l6C.

B. 2a-acetoxy-2-carboxyvinyl)-3B-hydroxy-5-oxo-IB- cyclopentaneheptanoicacid methyl ester. G-Iactone. S-cyclic ethylene acetal The ozonolysisproduct is acetylated in 6 ml. of pyridine and 3 ml. of acetic anhydrideat room temperature for l7 hours. 6 Ml. of xylene is added and thereaction mixture evaporated to dryness in vacuo. The residue istriturated with ether-hexane affording crystalline (1')-2a-(2-acetoxy-2-carboxyvinyl)JB-hydroxy-S-oxo-lli cyclopentaneheptanoicacid methyl ester. lS-laclone. S-cyclic ethylene acetal m.p. 8284C.

When in the above procedure optically active-Zu-t 2-carboxy-Z-formylethyl)-3B-hydroxy-5-oxo-IB- cyclopentaneheptanoic acidmethyl ester. fi-lactone. 5-cyclic ethylene acetal is employed in placeof the racemic mixture. there is obtained (+l-2a-(2-acetoxy-2-carboxyvinyl)-3B-hydroxy-5-oxo- IB- cyclopentaneheptanoic acid methylester. filactone, 5-cyclic ethylene acetal [al"""+30 f the naturalweries.

EXAMPLE 7 2a formyl-3[3-[(methoxalyl)oxyhS-oxo-IB- cyclopentaneheptanoicacid methyl ester. S-cyclic ethylene acetal l4. Mg. of osmium tetroxidein L4 ml. of methanol is added to a stirred solution of 430 mg. of(t)-2a-(2- acetoxy-Z-carboxyvinyl l-JB-hydroxy-ioxol B-cyclopentaneheptanoic acid methyl ester. fi-lactone. S-cyclic ethyleneacetal in i6 ml. of methanol. The reaction mixture darkens in l0-l5minutes and 440 mg. of powdered sodium periodate is added portionwiseover 3 hours. The reaction mixture is stirred for l additional hour.filtered, and the filtrate evaporated to dryness in vacuo. The residueis dissolved in 2.5 ml. of l:l ethyl accetate-benzene and the solutionwashed with water and saturated aqueous sodium chloride. The organiclayer is dried over sodium sulfate and evaporated to dryness in vacuoaffording '-)-2a-l'ormyl-3B-[(methoxa'lylloxyI-S-oxo-lB-cyclopentaneheptanoic acid methyl ester.cyclic ethylene acetal as an oil.

When in the above procedure (i)-2a(2-acetoxy-2-carboxyvinyldflhydroxy-S-oxol B- cyclopentaneheptanoic acid methylester. fi-lactone, S-cyclic ethylene acetal is employed in place of theracemic mixture, there is obtained opticallyactive-2aformyl-BB-l(methoxalyl)oxyl-S-oxo-lflcyclopentaneheptanoic acidmethyl ester. S-cyclic ethylene acetal. of the natural series.

EXAMPLE 8 3B-Hydroxy-2a-(3-oxo-l-octenyl)-5-oxo-lficyclopentaneheptanoicacid methyl ester. S-cyclic ethylene acetal A. 3134 methoxalyl)oxy}-2a-( 3-oxol -octenyl )-$-oxol B- cyclopentaneheptanoic acid methylester. S-cyclic ethylene acetal 230 Mg. of dimethyl-Z-oxoheptylphosphonate in 4 ml. of tetrahydrofuran is added to a stirred suspensionof 50 mg. of 50% sodium hydride dispersion in 10 ml. of tetrahydrofuranunder a nitrogen atmosphere at 0C. The reaction mixture is stirred at0C. for minutes and a solution of 420 mg. of (i)-2a-formyl-3B-[(methoxalyl )oxyl-S-oxo-l B-cyclopentaneh'eptanoic acid methyl ester,5-cyclic ethylene acetal in 4 ml. of tetrahydrofuran is added dropwiseover 5 minutes. After 10 minutes the mixture is allowed to warm to roomtemperature and stirred for 2 hours. The reaction is cooled to 10C..added to cold saturated aqueous sodium dihydrogen phosphate andextracted with ethyl acetate. The organic extract is washed withsaturated aqueous sodium chloride. stirred over sodium sulfate. andevaporated to dryness in vacuo affording (2)65-[(methoxalyl)oxy]-2a-(3-oxo-l-octenyl)-5-oxo- IB- cyclopentaneheptanoicacid methyl ester. S-cyclic ethylene acetal containing a smaller amountof (2)48- hydroxy-2a-( S-oxol -octenyl l-S-oxo- IB-cyclopenlaneheptanoic acid methyl ester. S-cyclic ethylene acetal.

B. 3B-Hydroxy-2a-(3-oxo-l-octenyll-S-oxo-IB- cyclopentaneheptanoic acidmethyl ester. S-cyclic ethylene acetal The above mixture is dissolved in7.5 ml. of methanol and 60 mg. of ethylenediamine in 5 ml. of methanoladded dropwise at 0C. The reaction mixture is stirred for 45 minutes at20C. and the solvent removed in vacuo. The residue is partitionedbetween ethyl acetate and saturated aqueous sodium dihydrogen phosphate.The layers are separated and the aqueous layer extracted with ethylacetate. The combined extracts are dried and evaporated to dryness invacuo. The residue is chromatographed on g. of silica gel eluting with30% acetone and chloroform taking fractions of 4 ml. each. Fractions5-l4 are combined and evaporated to dryness in vacuo affording 250 mg.of pure (1)48- hydroxy-2a-( 3-oxol -octenyl )-5-oxol B-cyclopentaneheptanoic acid methyl ester. S-cyclic ethylene acetal.Amaze. (methanol)==232nm (El2.500).

When in the above procedure. optically active-3B- I methoxalyl )oxyl-5-oxolfl-cyclopentaneheptanoic acid methyl ester. 5-cyclic ethyleneacetal of the natural series is employed in place of the raeemicmixture. there is obtained optically active-(IlB-hydroxy-2a(3- oxol-octenyl )-5 -oxolB-cyclopentaneheptanoic acid methyl ester. S-cyclicethylene acetal.

EXAMPLE 9 Prostaglandin 5.. methyl ester. cyclic ethylene acetal.l3B-hydroxy-2a-( 3 [S l'hydroxyl -octenyl)-S-oxo-IB-cyclopentaneheptanoic acid methyl ester, S-cyclic ethylene acetal] 23Mg. of sodium borohydride in 2 ml. of methanol at l0C is added dropwiseto a stirred solution of 245 mg. of(:)-3B-hydroxy-2a-(3-oxo-l-octenyU-S-oxolB-cyclopentaneheptanoic acidmethyl ester. S-cyclic ethylene acetal in 6 ml. of methanol at IOC. Thereaction mixture is stirred for 40 minutes at lC. and added to 50 ml. ofsaturated sodium dihydrogen phosphate and extracted with ethyl acetate.The extracts are washed with saturated aqueous sodium chloride. driedover sodium sulfate, and evaporated to dryness in vacuo. The residue ischromatographed on 20 g. of silica gel eluting with 50%acetone-chloroform and collecting 50 fractions of 3 ml. each. Fractions8-I8 are combined and evaporated to dryness affording (:)-3,6-hydroxy-Za-(BlRlhydroxy-l-octenyD-S-oxo-IB- cyclopentaneheptanoic acidmethyl ester. S-cyclic ethylene acetal. The 3fi[R]isomer (I00 mg.) isdissolved I in 5 ml. of ethyl acetate and stirred with 2 g. of activatedmanganese dioxide for 6 hours. The mixture is filtered. the precipitatewashed with acetone and the combined filtrates and washings evaporatedto dryness in vacuo affording recyclicable (:l-BB-hydroxy-2a-(3- oxo- I-octenyl)-5-oxol B-cyclopentanehaptanoic acid methyl ester. 5-cyclicethylene acetal.

Fractions 2l25 are combined and evaporated to dryness affording(i)-3B-hydroxy-2a-(3[SI-hydroxyl-octenyl )-5-oxo- IB-cyclopentaneheptanoic acid methyl ester. S-cyclic ethylene acetal m.p.54-56"C.

When in the above procedure optically active'ilfihyd roxy-ZB-l 3-oxo-l-octenyl )-5 -oxol B- cyclopentaneheptanoic acid methyl ester. 5-cyclicethylene acetal is employed in place of the racemic mixture. there isobtained optically active prostanglandin E methyl ester. cyclic ethyleneacetal. [BB-hydroxy- 2a-( 3! SJ-hydroxy- I -octenyl)-5-oxol B-cyclopentaneheptanoic acid methyl ester. S-cyclic ethylene acetal] ofthe natural series. m.p. 48-5lC.

EXAMPLE l0 Prostaglandin E.. cyclic ethylene acetal.[3B-hydroxy-2a-(3(S1hydroxy-l -octenyl)-5-oxo- 1B-oxocyclopentaneheptanoic acid. S-cyclic ethylene acetal] A solution of45 mg. of potassium hydroxide in 2.5 ml. of water at OC. is addeddropwise to a solution of 40 mg. of(2:)-3fl-hydr0xy-2oz-(3[S]hydroxy-loctenyl)-5-oxo-lB-cyclopentaneheptanoicacid methyl ester, S-cyclic ethylene acetal in l ml. of methanol at 0C.in a nitrogen atmosphere. The reaction mixture is allowed to warm toroom temperature and stirred for 3 hours. Cold dilute aqueous potassiumbicarbonate is added to the reaction mixture and the mixture extractedwith hexane. Solid sodium dihydrogen phosphate is added to the aqueouslayer and the latter is extracted with l:l ethyl acetate-benzene. Theorganic layer is dried over sodium sulfate and evaporated to dryness invacuo affording (:)-prostaglandin E,, 5- cyclic ethylene acetal[(:)-3B-hydroxy-2a-(3[S]-hydroxy-l-octenyl)-5-oxo-lfloxocyclopentanehaptanoic acid. S-cyclicethylene acetall m.p. 8284'C.

When in the above procedure optically active 38-hydroxy-Za-(BISlhydroxy-l-octenyl)-5-oxo-lflcyclopentaneheptanoic acidmethyl ester. $-cyclic ethylene acetal of the natural series is employedin place of the racemic mixture there is obtained optically activeprostaglandin E,. S-cyclic ethylene acetal of the natural series. m.p.8|-83C.

EXAMPLE I l Prostaglandin E,

A mixture of 37 mg. ofltl-prostaglandin E S-cyclic ethylene acetal and 3ml. of h! acetic acid-water is stirred at 25C. for 3 hours. Saturatedaqueous sodium hydrogen phosphate solution is added and the reactionmixture extracted with lzl ethyl acetate-benzene. The organic layer iswashed with saturated aqueous sodium chloride. dried over sodium sulfateand evaporated to dryness in vacuo affording a crystalline residue whichis recrystallized from ethyl acetate-benzene affording (:)-prostaglandinE... m.p. llI-l l3C.

When in the above procedure optically active prostaglandin E cyclicethylene acetal of the natural series is employed in place of theracemic mixture. there is obtained ()-prostaglandin E.. m.p. l I2l I3C..lal 58.

What is claimed is: i

l. 3B-Hydroxy-2a-( 3-oxo I -octenyl )-5-oxo- IB- cyclopentaneheptanoicacid. S-cyclic ethylene acetal. and stereoisomers and loweralkyl [oraralkyl] esters thereof.

2. The compound of claim I in which the Ioweralltyl ester is the methylester.

3. The process for the preparation of the compound of claim I whichcomprises treating the loweralkyl or aralkyl ester of3B-[(methoxalyl)oxy]-2a-( 3-oxo-loctenyll-s-oxo lB-cyciopentaneheptanoicacid. 5- cyclic ethylene acetal with a l.2-diamine.

i I U U i UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENTNO. 3,915,994

DATED October 28, 1975 |NVENTOR(S) 1 Norman L. Wendler, et al.

it is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 22, Line 39, delete the phrase [or aralkyl] Signed and Scaledthis [SEAL] Arrest:

RUTH C. MASON ('mmnr'ssr'mwr of Parents and Trademarks twenty-fourth D aOf February 1 9 76

1. 3B-HYDROXY-2A-(3-OXO-1-OCTENYL)-5-OXO-1B-CYCLOPENTANEHEPTANOIC ACID,5-CYCLIC ETHYLENE ACETAL, AND STEREOISOMERS AND LOWERLAKYL (OR ARALKYL)ESTERS THEREOF.
 2. The compound of claim 1 in which the loweralkyl esteris the methyl ester.
 3. The process for the preparation of the compoundof claim 1 which comprises treating the loweralkyl or aralkyl ester of 3Beta -((methoxalyl)oxy)-2 Alpha -(3-oxo-1-octenyl)-5-oxo-1 Beta-cyclopentaneheptanoic acid, 5-cyclic ethylene acetal with a1,2-diamine.